Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer
Abstract
T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.
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Intranodal vaccination with free mRNA encoding ten neoepitopes of 13 patients with metastatic melanoma generated T cell immunity against multiple neoepitopes in all patients.
“For example, intranodal vaccination with free mRNA encoding ten neoepitopes of 13 patients with metastatic melanoma generated T cell immunity against multiple neoepitopes in all patients209.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [209]
A first-in-human trial demonstrated clinical feasibility and safety of personalized mRNA cancer vaccines for advanced melanoma, with all vaccinated patients developing CD4+ and CD8+ T cell responses against selected antigens and some showing objective antitumor responses.
“A first-in-human trial demonstrated the clinical feasibility and safety of this approach for advanced melanoma cancers: all vaccinated patients developed CD4 + and CD8 + T cell responses against the selected antigens, with some patients showing objective antitumor responses [15].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [15]
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- Authors
- Sahin, U., Derhovanessian, E., Miller, M., Kloke, B.-P., Simon, P., Löwer, M., Bukur, V., Tadmor, A. D., Luxemburger, U., Schrörs, B., Omokoko, T., Vormehr, M., Albrecht, C., Paruzynski, A., Kuhn, A. N., Buck, J., Heesch, S., Schreeb, K. H., Müller, F., Ortseifer, I., Vogler, I., Godehardt, E., Attig, S., Rae, R., Breitkreuz, A., Tolliver, C., Suchan, M., Martic, G., Hohberger, A., Sorn, P., Diekmann, J., Ciesla, J., Waksmann, O., Brück, A.-K., Witt, M., Zillgen, M., Rothermel, A., Kasemann, B., Langer, D., Bolte, S., Diken, M., Kreiter, S., Nemecek, R., Gebhardt, C., Grabbe, S., Höller, C., Utikal, J., Huber, C., Loquai, C., & Türeci, Ö.
- Affiliations
- BioNTech (Germany) (DE)
- Johannes Gutenberg University Mainz (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Medical University of Vienna (AT)
- German Cancer Research Center (DE)
- ORCID
- Venue
- Nature
- Published
- 2017-07-05
- Volume
- 547
- Issue
- 7662
- Pages
- 222-226
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2724264513
- Cited by
- 2,488
- References
- 43
- Citations by year
- 2026: 228 · 2025: 255 · 2024: 259 · 2023: 299 · 2022: 277 · 2021: 317 · 2020: 290 · 2019: 262 · 2018: 239 · 2017: 58 · 2015: 1
- FWCI
- 105.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- neoantigens, melanoma, cancer immunotherapy, T cell response, metastasis prevention, anti-PD-1 therapy, acquired resistance, beta2-microglobulin deficiency, vaccine safety and tolerability, tumor cell killing, tumor-infiltrating T cells
- MeSH terms
- Nivolumab, Antibodies, Monoclonal, Epitopes, beta 2-Microglobulin, Humans, Immunotherapy, Melanoma, Mutation, Neoplasm Metastasis, Neoplasm Recurrence, Local, RNA, T-Lymphocytes, Vaccination, CD8 Antigens, Cancer Vaccines, Precision Medicine, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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